1. Field of the Invention
The present invention relates to the synthesis of crosslinked polymers. More particularly, the present invention relates to biodegradable crosslinked hydrogel copolymers.
2. Related Art
Interest in the synthesis of new degradable polymers has expanded in recent years. The increased interest in the synthesis of new degradable polymers stems in part from the use of synthetic polymers in medical applications. In many medical applications, it is advantageous that the polymer be able to degrade and that the degradation products also must be compatible with the human body, i.e., be nontoxic. In this situation, the polymers are termed biodegradable, indicating their ability to degrade due to biological processes occurring inside the human body. As early as the 1960s, synthetic polymers were used in the field of surgical medicine as suture material. The polymeric suture material was both biodegradable and absorbable, that is, the polymers decomposed after a period of time after implantation in the human body, and those decomposition products were absorbed by the human body without any adverse or toxic effects.
In addition to use as suture material, degradable polymers have been used in other biomedical applications, such as polymer-based drug delivery systems. In such a system, degradable polymers are used as a matrix for the controlled or sustained delivery or release of biologically active agents, such as protein drugs, to the human body. In addition, the development of endoscopic surgical techniques has resulted in the need for developing such degradable drug delivery systems wherein the placement of the drug delivery device is targeted for specific anatomical locations. Examples of such polymer-based drug delivery systems are described in the following U.S. patents: U.S. Pat. No. 6,183,781, entitled xe2x80x9cMethod for Fabricating Polymer-based Controlled-release Devicesxe2x80x9d; U.S. Pat. No. 6,110,503, entitled xe2x80x9cPreparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agentxe2x80x9d; U.S. Pat. No. 5,989,463, entitled xe2x80x9cMethods for Fabricating Polymer-based Controlled-release Devicesxe2x80x9d; U.S. Pat. No. 5,916,598, entitled xe2x80x9cPreparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agentxe2x80x9d; U.S. Pat. No. 5,817,343, entitled xe2x80x9cMethod for Fabricating Polymer-based Controlled-release Devicesxe2x80x9d; U.S. Pat. No. 5,650,173, entitled xe2x80x9cPreparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agent.xe2x80x9d Other examples of polymer-based drug delivery systems are described in U.S. Pat. No. 5,922,253, entitled xe2x80x9cProduction Scale Method of Forming Microparticlesxe2x80x9d and U.S. Pat. No. 5,019,400, entitled xe2x80x9cVery Low Temperature Casting of Controlled Release Microspheres,xe2x80x9d the technology described therein also known as Prolease(copyright). All of the above-identified patents are assigned to Alkermes Controlled Therapeutics, Inc. of Cambridge, Mass., and are incorporated herein by reference.
Degradable polymers have also been used in other biomedical applications, including use as polymer scaffolds for tissue engineering, and are described in U.S. Pat. No. 6,103,255, for example, incorporated herein by reference. Additional biomedical applications for synthetic biodegradable polymers include use with fracture fixation, for example, as absorbable orthopedic fixation devices, and are described in U.S. Pat. Nos. 5,902,599 and 5,837,752, both of which are incorporated herein by reference. Synthetic biodegradable polymers are also used in dental applications, and are described, for example, in U.S. Pat. No. 5,902,599.
The wide variety of biomedical applications just described for synthetic biodegradable polymers demonstrates the need for the development of different types of polymers with varying physical properties for use in various biomedical applications.
Synthetic degradable absorbable polymers already developed to date for use in biomedical applications include, for example, poly(p-dioxanone), which is an alternating ether-ester polymer, and its copolymers; polycaprolactone; polyhydroxyalkanoates; poly(propylene fumarate); poly(ortho esters); other polyesters including poly(block-ether esters), poly(ester amides), poly(ester urethanes), polyphosphonate esters, and polyphosphoesters; polyanhydrides; polyphosphazenes; poly(alkylcyanoacrylates); and polyacrylic acids, polyacrylamides, and their hydrogels. These synthetic absorbable polymers are discussed in detail in Handbook of Biodegradable Polymers, edited by Domb, Kost, and Wiseman (Harwood Academic Pub. 1997), incorporated herein by reference.
In addition, synthetic polymers based on the polymerization of caprolactone, lactic acid, and glycolic acid have become mainstays in the field of degradable polymers, in particular the field of degradable polyesters, and are available commercially. Caprolactone is the cyclic ester derivative of hydroxy caproic acid, HO(CH2)5CO2H, and can be ring-opened to form the polyester poly(caprolactone), xe2x80x94[O(CH2)5CO2]xe2x80x94. It should be noted that caprolactone has two structural isomers, designated xcex5- and xcex4-caprolactone. Any discussion of caprolactone generally applies to both forms, unless specifically noted.
Polylactide, polyglycolide, and the copolymers of lactide with glycolide are known for their applications as biodegradable polymers because of their proven biocompatibility and versatile degradation properties. Lactic acid- and glycolic acid-based polymers with high molecular weights are not obtained through direct condensation of the corresponding carboxylic acid due to reversibility of the condensation reaction, backbiting reactions, and the high degree of conversion required. Rather, lactic acid- and glycolic acid-based polymers are typically obtained by ring-opening polymerization of the corresponding diester dimers, lactide and glycolide, respectively, themselves. Alternatively, the reaction can be carried out as a condensation of lactic and glycolic acid. The resulting polymers of these polymerization reactions are poly(lactic acid), also referred to as poly(lactide), abbreviated PLA and poly(glycolic acid), also referred to as poly(glycolide), abbreviated PGA. Copolymers incorporating both monomers are also available and are termed poly(lactide-co-glycolides) abbreviated PLGA and poly(glycolide-co-lactides) abbreviated PGLA, or collectively PLGs. U.S. Pat. No. 5,650,173, incorporated herein by reference, describes examples of these commercially available polymers and copolymers based on lactic acid and glycolic acid. It should be noted that lactide has two structural isomers, denoted D and L. Any discussion of lactide generally is referring to a racemic mixture of both isomers, i.e., D,L-lactide, abbreviated DLLA, unless specifically noted.
All of these polymers and copolymers derived from caprolactone, lactic and glycolic acid contain ester linkages in the backbone of the polymer chain. The presence of this ester linkage provides the necessary functionality to permit degradability, particularly biodegradability in the human body. As opposed to other linkages, such as amides, which require severe conditions in order to decompose, the ester linkage undergoes hydrolysis under even mildly basic conditions such as those found in vivo. In contrast, the amide linkage requires more stringent conditions and is not easily hydrolyzed even under strongly acidic or basic conditions. In vivo, the only available route for cleavage of an amide bond is enzymatic, and that cleavage is often specific to the amino acid sequence. The highly crystalline nature of polyamides, e.g., nylon, further slows degradation by preventing or blocking access to the amide bond by water molecules and enzymes.
While these polymers based on lactide, glycolide, and/or caprolactone offer advantages in degradability as just discussed, they also suffer from the disadvantage that they are hydrophobic, i.e., they do not readily absorb or take up water molecules. For example, polylactide has a very low water uptake of about 5 weight percent due to its high hydrophobicity. As a result, their applicability for use as drug delivery systems and compatibility with living systems can be limited.
One polymer system that is compatible with living systems and does readily absorb water is the hydrogels. Hydrogels are three-dimensional networks, composed of homopolymers or copolymers, that are capable of absorbing large amounts of water or biological fluids. A characteristic of hydrogels is that they swell in water without dissolving. Their high water content and soft consistency make hydrogels similar to natural living tissue more than any other class of synthetic biomaterials. Thus, hydrogels have found numerous applications especially in medical and pharmaceutical sectors. Hydrogels have been investigated widely as drug carriers due to their adjustable swelling capacities, which permit flexible control of drug release rates.
However, hydrogel networks are generally insoluble due to the presence of chemical crosslinks (i.e., nodes or junctions) or of physical crosslinks (i.e., entanglements). As a result, most hydrogels are not biodegradable, which limits their clinical use in the human body. Examples of nonbiodegradable hydrogels include poly(N-isopropyl acrylamide), poly(hydroxy ethylmethacrylate), poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof. Incorporation of chemically hydrolyzable or biochemically cleavable groups into the polymer network structure is one of the methods used to prepare biodegradable hydrogels. Examples of such hydrogels are described in U.S. Pat. No. 5,626,863, issued to Hubbell et al., entitled xe2x80x9cPhotopolymerizable Biodegradable Hydrogels as Tissue Contacting Materials and Controlled-Release Carriersxe2x80x9d; U.S. Pat. No. 5,844,016, issued to Sawhney et al., entitled xe2x80x9cRedox and Photoinitiator Priming for Improved Adherence of Gels to Substratesxe2x80x9d; U.S. Pat. No. 6,051,248, issued to Sawhney et al., entitled xe2x80x9cCompliant Tissue Sealantsxe2x80x9d; U.S. Pat. No. 6,153,211, issued to Hubbell et al., entitled xe2x80x9cBiodegradable Macromers for the Controlled Release of Biologically Active Substancesxe2x80x9d; U.S. Pat. No. 6,201,065, issued to Pathak et al., entitled xe2x80x9cMultiblock Biodegradable Hydrogels for Drug Delivery and Tissue Treatmentxe2x80x9d; U.S. Pat. No. 6,201,072, issued to Rathi et al, entitled xe2x80x9cBiodegradable Low Molecular Weight Triblock Poly(lactide-co-glycolide) Polyethylene Glycol Copolymers Having Reverse Thermal Gelation Properties.xe2x80x9d All of the aforementioned patents are incorporated herein by reference. Nevertheless, the nonbiodegradability of hydrogel networks remains an obstacle in the further development of using hydrogels in biomedical applications, in particular, drug delivery systems.
Thus, while hydrogels are advantageously hydrophilic, they are disadvantageously difficult to biodegrade. Conversely, while polymers based on lactide and/or glycolide are advantageously biodegradable, they are disadvantageously hydrophobic.
In order to address the hydrophobicity of the polymers based solely on caprolactone, lactic acid and glycolic acid, degradable polymers can be synthesized in which additional monomer units are incorporated into the backbone of poly(caprolactone), PLA, PGA, or PLGs. In particular, copolymerization with preformed polymers having a hydrophilic segment can be used. Such hydrophilic segments include any number of segments based on diol- or glycol- containing linkages, for example, polyethylene glycol (PEG), also known as polyethylene oxide (PEO), polypropylene oxide (PPO), and pluronics. The resulting copolymers, thus include lactide and/or glycolide monomer units along with the polyether hydrophilic core initiating segment as a single block in the backbone of the polymer. For example, a PEG with molecular weight of 600 would consist of a block of at least 13 monomer units. Other polymers have multiple large segments or blocks of PEG alternating with blocks of a polyester. For example, Polyactive(copyright) is a copolymer that has large blocks of PEG alternating with blocks of poly(butylene terephthalate).
Other examples of lactide-based polymers that include a hydrophilic segment include the following: U.S. Pat. Nos. 4,526,938 and 4,745,160 to Churchill et al. disclose the synthesis of polylactide block copolymers with poly(ethylene glycol) or pluronics, in which the molecular weights of the hydrophilic segments are more than 5000 Daltons. U.S. Pat. No. 5,702,717 to Cha et al. and U.S. Pat. No. 6,117,949 to Ramesh et al. report thermogelling polymers of the same type with molecular weights of the hydrophilic segments (i.e., PEG) lower than 5000 Daltons. Subsequently, PCT/US00/32130 (WO 01/41735) to Shah et al. discloses the synthesis of polymers based on triblock copolymers of low molecular weight pluronics with PLGA. All of the foregoing patents and published patent applications are incorporated herein by reference. All of the polymers disclosed in these patents, while having improved hydrophilicity due to the presence of PEG or pluronics, are nevertheless linear polymers containing only physical, rather than chemical, crosslinks. Such physical crosslinks are due to the interaction between chains of the polymer and the different parts of the polymer""s building blocks. The lack of chemical crosslinks between polymer chains may limit the formation of a variety of three-dimensional networks that could advantageously be manipulated for use in drug delivery systems and other applications where control of water content is important.
Crosslinking linear polymer chains is frequently accomplished through the introduction of an additional block in the copolymer backbone that has functionality capable of reacting chemically with functionality on another linear polymer chain. Epoxides, i.e., molecules containing the oxirane functionality, i.e., a three-membered Cxe2x80x94Oxe2x80x94C ring, are known to undergo ring-opening polymerization reactions in the same manner and under the same conditions as the ring-opening polymerization of cyclic esters, i.e., lactide, glycolide, and caprolactone. In particular, the ring-opening polymerization of epoxides takes advantage of the fact that cyclic monomers inherently have associated ring strain, which is inversely proportional to the size of the ring. The greater the ring strain, the less energy required to open the ring, and the milder the reaction conditions necessary to achieve polymerization. Thus, copolymerizing a functionalized epoxide and a cyclic ester incorporates the ring-opened epoxide into the backbone of the linear copolymer. Choice of appropriate functionality on the epoxide may permit subsequent crosslinking of the linear copolymer chains.
One example of using epoxides to produce copolymers is described in U.S. Pat. No. 4,195,167, issued to Knopf et al., entitled xe2x80x9cGradient Polymers of Two or More Cyclic, Organic, Ring-Opening, Addition Polymerizable Monomers and Methods for Making Same.xe2x80x9d This patent, incorporated herein by reference, describes the formation of copolymers of ethylene oxide and propylene oxide using a basic catalyst, e.g., potassium hydroxide, at temperatures above 100xc2x0 C.
Another example of using epoxides to produce copolymers is described in U.S. Pat. No. 6,221,977, issued to Park et al., entitled xe2x80x9cBiodegradable Aliphatic Polyester Grafted with Polyether and a Process for Preparing the Same.xe2x80x9d This patent, incorporated herein by reference, describes the formation of grafted polymers wherein an epoxide, i.e., epichlorohydrin, is reacted with polyethyleneglycolmethylether (PEGME), to form an epoxide substituted with a polyether linkage. That substituted epoxide is then reacted with an ester to form a polyester polymer grafted to a side chain composed of PEGME through an ether linkage.
Another example involving epoxides to produce copolymers is described in an article by Jeong et al., entitled xe2x80x9cThermogelling Biodegradable Polymers with Hydrophilic Backbones: PEG-g-PLGA,xe2x80x9d in Macromolecules, 2000, 33, 8317-22. That article, incorporated herein by reference, describes the sequential synthesis of a copolymer using preformed PEG in the backbone grafted to side chains derived from lactide and glycolide.
Another example where epoxides have been used to form copolymers is described in U.S. Pat. No. 5,359,026, issued to Gruber, entitled xe2x80x9cPoly(Lactide) Copolymer and Process for Manufacture Thereof.xe2x80x9d That patent, incorporated herein by reference, describes copolymerization of lactide with an epoxidized fat or oil, e.g., linseed oil, for the purpose of forming copolymers with improved processing properties. However, the epoxides disclosed in that patent are not functionalized. Moreover, those epoxides are actually multiple epoxides (polyepoxides), rather than monomeric epoxides, when reacted with lactide, requiring temperatures in excess of 180xc2x0 C.
Another example of copolymerizing epoxides and lactides and/or glycolides is described in U.S. Pat. No. 4,644,038, issued to Protzman, which is incorporated herein by reference. In particular, the epoxide monomers described in this patent contain vinyl groups, i.e., the epoxide monomers are ethylenically unsaturated. In a subsequent reaction, the linear copolymers are crosslinked to form chemical bonds, forming a network. However, while this patent involves the crosslinking of epoxide and lactide/glycolide copolymers, this patent does not address the incorporation of hydrophilic segments into the polymer network in order to affect the ability of that network to absorb water. In particular, none of the crosslinked polymers described therein are hydrogels. Moreover, none of the crosslinked polymers described therein are used in drug delivery systems.
Other examples of including functionality in the polymer backbone to effect crosslinking in a subsequent reaction, i.e., through photocuring, radiation, or by chemical means, other than by incorporating functionalized epoxides, exist. Examples of such crosslinkable polymeric systems are the following: U.S. Pat. No. 5,626,863, issued to Hubbell et al., entitled xe2x80x9cPhotopolymerizable Biodegradable Hydrogels as Tissue Contacting Materials and Controlled-Release Carriersxe2x80x9d; U.S. Pat. No. 5,844,016, issued to Sawhney et al., entitled xe2x80x9cRedox and Photoinitiator Priming for Improved Adherence of Gels to Substratesxe2x80x9d; U.S. Pat. No. 6,051,248, issued to Sawhney et al., entitled xe2x80x9cCompliant Tissue Sealantsxe2x80x9d; U.S. Pat. No. 6,153,211, issued to Hubbell et al., entitled xe2x80x9cBiodegradable Macromers for the Controlled Release of Biologically Active Substancesxe2x80x9d; U.S. Pat. No. 6,201,065, issued to Pathak et al., entitled xe2x80x9cMultiblock Biodegradable Hydrogels for Drug Delivery and Tissue Treatment.xe2x80x9d All of the aforementioned patents were previously incorporated herein by reference.
In particular, U.S. Pat. No. 5,410,016, issued to Hubbel et al., entitled xe2x80x9cPhotopolymerizable Biodegradable Hydrogels as Tissue Contacting Materials and Controlled-Release Carriers,xe2x80x9d and incorporated herein by reference, describes the synthesis of crosslinked hydrogels of polylactide-block-poly(ethylene glycol)-block-polylactide via a three step process. In the first step, polymerization of lactide and/or glycolide was initiated using poly(ethylene glycol) and a stannous octoate catalyst system. In the second step, these block copolymers were end-capped with acryloyl chloride to incorporate unsaturation at the ends of the linear polymer chains. In a third step, these vinyl end-capped polymers were crosslinked. This three-step process is outlined below in Scheme 1, wherein the brackets labeled PLA indicate the lactide backbone of the copolymer. 
This patent describes the incorporation of unsaturated groups in the linear polymer chains by means of reaction of the hydroxyl groups at the chain ends with acrylic acids or chlorides. The result is the presence of ethylenic unsaturation only at the ends of the linear polymer chains. Any subsequent crosslinking reaction will only result in crosslinks at the ends of the linear polymer chains. This provides minimal control over the degree of crosslinking and thus minimal control over the properties of the resulting polymer network, in particular, the ability of the network to absorb water and the ability of the network to act as a drug delivery system. This patent describes neither the incorporation of unsaturated groups into the polymer backbone by using a bifunctional ring-opening polymerizable monomer, such as an ethylenically unsaturated epoxide, nor that that incorporation is random inside the copolymer backbone, thereby creating multiple sites for potential future crosslinking reactions.
Thus, there is a need to develop biodegradable polymer systems, based on ring-opened cyclic esters, that not only contain hydrophilic segments capable of absorbing significant amounts of water, but also contain sufficient functionality to facilitate crosslinking reactions in order to form three-dimensional networks. The present invention, the description of which is fully set forth below, solves the need in the art for development of such biodegradable crosslinked hydrogel networks.
The present invention provides for the synthesis of various biodegradable copolymers. The copolymers are synthesized through the process of ring-opening polymerization.
In one embodiment of the invention, the copolymers synthesized through the process of ring-opening polymerization are comprised of a ring-opened cyclic ester, a ring-opened ethylenically unsaturated epoxide, and a hydrophilic segment. The ring-opened cyclic ester units contain the requisite ester functionality in the backbone of the polymer to readily permit degradation, in particular biodegradation. The ring-opened ethylenically unsaturated epoxide units are randomly distributed in the polyester backbone and contain unsaturated functionality to permit crosslinking and the formation of three-dimensional networks. The hydrophilic segment is also incorporated in the backbone of the polymer to enhance the hydrophilicity of the copolymer, resulting in a hydrogel network upon crosslinking.
In a further embodiment of the invention, the copolymers comprising a ring-opened cyclic ester, a ring-opened ethylenically unsaturated epoxide, and a hydrophilic segment are subsequently crosslinked, through the unsaturated functionality of the ring-opened epoxide, to form a three-dimensional network. The crosslinking can be accomplished by any known means, e.g., through photocuring, radiation, or by chemical means.
In still another embodiment, the present invention provides for a method of synthesizing biodegradable crosslinked polymer networks by means of a two-step synthesis: the first step is the ring-opening copolymerization of a cyclic ester and an ethylenically unsaturated epoxide in the presence of a hydrophilic segment, such that the ring-opened epoxide is randomly distributed in the polyester backbone; the second step is the crosslinking of the resulting copolymer linear chains. Polymerization in this way permits the incorporation of hydrophilic units into the polyester backbone, in order to impart desirable hydrogel characteristics to the copolymer, and then permits the crosslinking of copolymer chains to form a three-dimensional network. This synthetic procedure results in the synthesis of xcex1-hydroxy, e.g., lactide- and/or glycolide-based, biodegradable hydrogels.
Viewed from another aspect, the present invention provides for the synthesis of biodegradable crosslinked hydrogels that can be used for the controlled delivery of drugs, or any other biologically active agents, i.e., proteins, in a sustained manner. The present invention also provides for the use of such biodegradable crosslinked hydrogels as scaffolds in tissue engineering, tissue replacement, and tissue regeneration, as surgical sealants and tissue sealants for wound repair, as adhesives, and as coatings. The present invention contemplates in vivo as well as ex vivo applications.
Viewed from a further aspect, the present invention provides for mixing the copolymers with active agents before the copolymers are crosslinked. In this aspect of the invention, the copolymers are first mixed with active agents and then injected subcutaneously into a human patient. After injection, the copolymers are crosslinked in situ. One method of in situ crosslinking involves curing with ultraviolet radiation.
Viewed from yet a further aspect, the present invention provides for the preparation of crosslinked microparticles or implantable hydrogels that encapsulate the incorporated active agents.
The present invention advantageously can be used for the synthesis of biodegradable crosslinked hydrogel polymers heretofore unavailable. The synthetic methods of the present invention are easily adaptable to existing polymer synthesis protocols.
The present invention avoids the hydrophobicity of previous lactide- and/or glycolide-based polymers, while at the same time provides for the biodegradability of the resulting crosslinked hydrogel three-dimensional networks, which networks previously lacked acceptable degradation characteristics.
The present invention also provides for the random incorporation of unsaturated functionality into the polyester backbone of linear polymer chains, rather than merely at the ends of the polymer chains. As the amount of unsaturated functionality directly relates to the amount of subsequent crosslinking, controlling the incorporation of this unsaturation permits greater control over the physical properties of the resulting hydrogel, in particular, the consistency of the gel itself as well as the amount of gel obtained from the crosslinking of the original copolymers.
Moreover, as the quantity and type of hydrophilic segments in the polyester backbone of a linear polymer chain directly relate to the hydrophilicity of any resulting crosslinked polymer network, controlling the incorporation of the hydrophilic segments permits greater control over the physical properties of the resulting hydrogel, in particular, the water content of the gels as well as their equilibrium swelling ratios.
Additionally, because the result of the copolymerization is a polymer backbone that is a derivative of both polyethylene oxide and cyclic esters (i.e., the standard synthesis of degradable polyesters), toxicity issues should be minimal, if not nonexistent.
Also, control over the degree of hydrophilicity and the amount of crosslinking provides for improved polymer processing and use in a greater diversity of potential applications. The crosslinked hydrogels of the present invention can be processed to form particulates for delivery of active agents in pharmaceutical applications, and can be used as scaffolds in tissue engineering, tissue replacement, and tissue regeneration, as surgical sealants and tissue sealants for wound repair, as adhesives, and as coatings, involving both in vivo as well as ex vivo applications.